June io, 1922] 



NATURE 



751 



uch action ; the series of compounds which they 

 investigated included the acridine group, triphenyl- 

 inethane group, indamines, azine dyes (safranin), 

 tliiopyronin, and thiazines (methylene blue). A con- 

 tinuation of this work showed that of all the sub- 

 stances examined diaminoacridine derivatives (" acri- 

 fiavine " and " proflavine ") stand out on account 

 of a combination of three characteristics, namely, 

 high antiseptic potency, low toxicity for mammalian 

 tissues, and insusceptibility to the interfering action 

 of serum proteins, which diminish markedly the efficacy 

 of all other powerful antiseptics hitherto tested. 

 Therefore these substances, the antiseptic properties of 

 which had not been recognised before, have been widely 

 employed for the treatment of localised pyogenic 

 infections, e.g. in wounds ; when suitably applied, 

 their use has proved highly beneficial. Recently 

 also non-ionised compounds of mercury with dyes of 

 the eosin group have been successfully used in America 

 (mercurochrome of Young, White, and Swartz).^-^ 

 In the case of generalised infections, however, the 

 therapeutic problem is attended by much greater 

 difficulties, and there is probably no synthetic compound 

 so far available which will exert curative action in 

 generalised bacterial infections in the human subject. 



Selective Action. 

 When the antiseptic potency of a series of com- 

 pounds is determined for organisms of various types, 

 striking instances of selective action are met with, i.e. 

 one compound will act very powerfully upon a particular 

 organism and be relatively inert toward another ; 

 other compounds may exhibit the reverse order of 

 activity on the same two organisms. Selective action 

 of this kind was noted by Rozsahegyi ^ in 1887. Prob- 

 ably the most striking example of this is exhibited 

 by the cyanine dye, " sensitol red," the ratio of the 

 sterilising concentrations for B. coli and Staphylococcus 

 aureus being probably greater than 2000 : i (Browning, 

 Cohen, and Gulbransen).' 



Relationships between Chemical Constitution 



AND Antiseptic Action. 

 Within narrow limits, in groups of closely related 

 compounds, certain laws have been established. In 

 the triphenylmethane series, both with the diamino 

 and the triamino derivatives, the substitution of methyl 

 and ethyl groups in the amino radicals has been found 

 to enhance the antiseptic action. Thus the penta- 

 and hexamethyl triaminotriphenylmethane dyes, 

 methyl violet and crystal violet, have been found by 

 Dreyer, Kriegler and Walker ,8 and others to be more 

 potent against staphylococci than the unsubstituted 

 analogues, rosaniline or parafuchsine ; similarly 

 malachite green (the tetramethyl diamino derivative) 

 and brilliant green (tetraethyl derivative) are much 

 more powerful than the unsubstituted diaminotri- 

 phenylmethane dye, Doebner's violet.^ In the acridine 

 and azine series it has been established that potency of 

 action in a serum medium is a characteristic of the 

 diamino derivatives which have an alkyl group attached 

 to the medial nitrogen atom (Browning, Cohen, Gaunt, 

 and Gulbransen).^ But general principles correlating 

 chemical structure with antiseptic action cannot be 

 formulated in the present state of knowledge. There 



NO. 2745, VOL. 109] 



is certainly no relationship between colour and effect 

 on micro-organisms. 



Action on Protozoa. 



Ehrlich and Shiga ^° discovered that by means of 

 injections of a benzidine dye, which they named 

 trypan red, mice infected with the trypanosomes of the 

 South American horse disease, mal de caderas, could be 

 completely sterilised ; thereby an otherwise acutely 

 fatal infection could be cured. This work gave the 

 impetus to the search for chemotherapeutic agents, and 

 the greatest success achieved in this line has been the 

 discovery of the " salvarsan " group of compounds by 

 Ehrlich and his co-workers. In this department of 

 research, again, it is impossible so far to enunciate 

 general principles which should guide us in the search 

 for -effective substances. The therapeutic action is fre- 

 quently not simply that of an antiseptic operating in 

 the tissues and circulation of the infected animal ; 

 thus in vitro the parasites of mal de caderas are not 

 killed by concentrated solutions of trypan red. 

 Further, selective action is exhibited to a very marked 

 degree by chemotherapeutic agents in protozoal 

 infections ; the efficacy of quinine in malaria and its 

 relative inertness in trypanosomiasis is an instance of 

 this. Certain compounds, however, are lethal for 

 protozoa in vitro in concentrations which permit 

 bacteria, of some species at least, to survive. Fair- 

 brother and Renshaw suggest that such substances 

 may be utilised with advantage in circumstances in 

 which the process of bacterial purification of sewage 

 fails, owing, it is believed, to an overgrowth of certain 

 protozoa destroying the bacteria. 



The search for chemical substances which shall 

 exert curative effects in bacterial and protozoal infec- 

 tions appears to be well worth pursuing, since there are 

 many diseases in which it would seem to be impossible 

 to influence to a significant extent the natural defensive 

 mechanisms of the body by procedures of specific 

 immunisation ; tuberculosis is an outstanding instance. 

 But the successes hitherto achieved, especially in 

 protozoal and spirochaetal diseases (quinine in malaria, 

 salvarsan in syphilis and other spirochaetal infections, 

 trypan blue in piroplasmosis, and emetine in amoebic 

 dysentery), and the promising results in certain bacterial 

 diseases (diaminoacridine derivatives, triphenyl- 

 methane compounds and mercurochrome in local 

 pyogenic infections, and ethylhydrocuprein in experi- 

 mental pneumococcus infections) are still more or 

 less isolated phenomena. If it be possible to establish 

 general principles in chemotherapy, this result will 

 only be attained by much further investigation. 



References. 



1. Fairbrother and Renshaw, Times, March 31, 1922 ; Journ. Pathol, and 

 BacUriol., 1922, 25, p. 145. 



2. Stilling, Lancet, 1890, 2, p. 965 ; ib., 1891, i, p. 873. 



3. Churchman, Joum. Exper. Med., 1912, 15, p. 221 ; ib., 1921, 33, pp. 

 569 and 583. 



4. Drigalski and Conradi, Zeitschr. f. Hyg., 1902, 39, p. 283. 



5. Browning and Gihnour, Joum. Pathol, and Bactertol., 1913, 18, p. 144 ; 

 Browning, Gilmour, and Gulbransen in Browning's " Applied Bacteriology," 

 London, 1918, p. 65. 



5A. Young, White, and Swartz, Joum. Amer. Med. Assoc., Nov. 15, 1919. 



6. Rozsahegyi, Cenl.f. Bakt., 1887, 2, p. 418. 



7. Browning, Cohen, and Gulbransen, Brit. Med. Joum., 1922, i, p. 514. 



8. Dreyer, Kriegler, and Walker, Joum. Path, and Bactertol, 1910, 15, 

 p. 133. 



9. Browning, Cohen, Gaunt, and Gulbransen, Roy. Soc., B, 1922, 93, p. 329; 

 Browning and Cohen, Brit. Med. Joum., Oct. 29, 192 1. 



10. Ehrlich and Shiga, Berl. klin. Wochenschr., 1904, pp. 329, 362. 



